Title: Treatments for nervous disorders
United States Patent: 6,352,986
Inventors: Hassan; Fred (Bridge Water, NJ); McCall; John
Michael (Kalamazoo, MI); Taylor; Duncan Paul (Kalamazoo, MI); Von
Voigtlander; Philip F. (Plainwell, MI); Wong; Erik Ho Fong (Portage, MI)
Assignee: Pharmacia & Upjohn Company
Appl. No.: 565780
Filed: May 5, 2000
This patent application describes the treatment of Addictive Disorders,
Psychoactive Substance Use Disorders, Intoxication disorders, Inhalation
disorders, Alcohol addiction, Tobacco Addiction and or Nicotine Addiction;
and Attention Deficit Hyperactivity Disorder (ADHD); comprising
administering a therapeutically effective, nontoxic dose of Reboxetine and
derivatives and or pharmaceutically acceptable salts thereof to a patient.
DESCRIPTION OF THE INVENTION AND DESCRIPTION OF THE PREFERRED
Reboxetine is the generic name of the pharmaceutical substance with the
chemical name of 2-(I-((2-ethoxyphenoxy)benzyl)-morpholine, and its
pharmaceutically acceptable salts. Reboxetine can be a free base, or it
can include reboxetine methanesulfonate (also called reboxetine mesylate)
or any other pharmaceutically acceptable salt that does not significantly
affect the pharmaceutical activity of the substance. Reboxetine and a
method of synthesis are described in U.S. Pat. No. 4,229,449, issued Oct.
21, 1980, Melloni et. al., incorporated by reference, methods of
preparation are described in U.S. 5,068,433, issued Nov. 26, 1991, Melloni
et. al. and in U.S. Pat. No. 5,391,735, issued Feb. 21, 1995, both
incorporated by reference. Reboxetine may also be known under the trade
name of EDRONAX.TM..
The pharmaceutical compositions and methods of administration described in
U.S. 4,229,449 at col. 18, lines 33-66 are specifically incorporated by
reference. Twice a day dosing is preferred with current formulations.
Reboxetine acts as an antidepressant. Antidepressants are frequently
grouped into categories or "generations." The first generation
of antidepressants were usually tricyclic antidepressants such as
maprotiline that affected various neurotransmitter systems and are
associated with many undesirable side effects. The second generation of
antidepressants, such as mianserine, mirtrazapine and trazodone are
largely devoid of anticholinergic action and their adrenolytic and
antihistaminic effects are weaker. These are contrasted with the third
generation of antidepressants (e.g. SSRI, ipsapirone, viloxazine,
reboxetine, bupropione) that mediate only one of the three main
neurotransmitter system for depression (5-HT, noradrenaline, dopamine) and
they do not affect muscarine, histamine and adrenergic cerebral systems.
Svestka, J. "Antidepressives of the 3rd, 4th and 5th
generation," Cesk-Psychiatr. Febuary; 1994 90(1):3-19. (Czech).
Reboxetine however; does not act like most antidepressants. Unlike
tricyclic antidepressants and even selective serotonin reuptake inhibitors
(SSRIs), reboxetine is ineffective in the 8-OH-DPAT hypothermia test,
indicating that reboxetine is not a selective serotonin reuptake inhibitor
rather it is selective for the noradrenergic system. Thus, reboxetine is
not an SSRI, rather it is considered a novel, selective, noradrenaline-reuptake
inhibitor (NARI). Leonard-BE, "Noradrenaline in basic models of
depression." European-Neuropsychopharmacol. April; 1997 7 Suppl 1:
S11-6; discussion S71-3. Unlike most drugs, Reboxetine is a highly
selective norepinephrine uptake inhibitor, with only marginal serotonin
and no dopamine uptake inhibitory activity. The compound displays only
weak or no anti-cholinergic activity in different animal models and is
devoid of monoamine oxidase (MAO) inhibitory activity.
Reboxetine is highly potent and fast acting. Our investigations indicate
Reboxetine has potent antireserpine activity and combines the inhibitory
properties of classical tricyclic antidepressants on the reuptake of
noradrenaline with an ability to desensitize J-adrenergic receptor
function without showing any appreciable interaction with muscarinic
cholinergic and I-adrenerigic receptors. Moreover, Reboxetine shows less
vagolytic activity than other tricyclic antidepressants.
The inventors have discovered that, because of its unique properties,
Reboxetine has been found particularly useful for treating or enhancing
the treatment of a few psychiatric symptoms or disorders, with greater
efficacy and with fewer side effects, than are treated by known drugs.
Furthermore, the inventors here have also discovered that Reboxetine can
also be used to treat or to enhance the treatment of a few other specific
psychiatric symptoms or disorders. The symptoms or disorders amenable to
treatment with Reboxetine are provided below.
The dosage used to treat all of the disorders described here is as
follows. Reboxetine is well tolerated and has a wide safety range, it can
be administered in a dose range of active ingredient from about 1 to over
20 mg/kg. It is more commonly provided in dosages of from 1 to 20 mg per
patient per day. The compound may be administered by any suitable method
including a convenient oral dosage form. A preferred method is oral dosing
twice a day. The preferred dose range is 4 to 10 mg per patient per day
and the most preferred dose is 6 to 8 mg or 8 to 10 mg per patient daily,
depending upon the patient, delivered twice a day (b.i.d.). It can also be
given at dosages of 2, 4, 6, 8, 10 or 12 mg per patient per day or
fractions thereof: For example, suitable administrations could be 4 mg in
the morning and 2 or 4 mg in the evening or 6 mg in the morning and 4 mg
in the evening. In some patients the ideal dosing would be 3-5 mg in the
morning and 3-5 mg in the evening. A skilled practitioner would be
expected to determine the precise level of dosing. The ideal dosing would
be routinely determined by an evaluation of clinical trials and the needs
of the patient.
The diseases described for treatment here are:
I. Addictive Disorders and Psychoactive Substance Use Disorders, such as
Intoxication disorders, Inhalation disorders, Alcohol addiction, Tobacco
Addiction and or Nicotine Addiction. Tobacco and Nicotine addiction would
be treated with the goal of achieving either Smoking Cessation or Smoking
Addictive Disorders, Alcohol and Other Psychoactive Substance Use
Disorders, disorders related to Intoxication and Inhalants and especially
Tobacco Addiction or Nicotine Addiction, may be treated with Reboxetine.
Tobacco Addiction or Nicotine Addiction would be treated with Reboxetine
in order to achieve smoking/chewing cessation or smoking/chewing
reduction. General descriptions of Addictive Disorders, including
disorders related to Intoxication and Inhalants and Tobacco Addiction or
Nicotine Addiction may be found in many standard sources, such as, The
American Psychiatric Press Textbook of Psychiatry, Second Edition, Edited
by Robert E. Hales, Stuart C. Yudofsky, and John A. Talbott, copyright
1994, incorporated by reference, especially pp. 401 et. seq., section on
"Nicotine" incorporated by reference. Another of many texts is
the Manual of Psychiatric Therapeutics, Second Edition, edited by Richard
I. Shader, incorporated by reference, especially pp. 85 from Chapter 11
The treatment of Alcohol and Other Psychoactive Substance Use Disorders,
such as disorders related to Intoxication and Inhalants and Tobacco
Addiction or Nicotine Addiction but especially Tobacco Addiction involves
the administration of Reboxetine in a manner and form that provide a
reduction in the symptoms of the disease. Tobacco Addiction or Nicotine
Addiction in particular would be treated to achieve a reduction or
cessation of smoking or chewing of nicotine containing materials by a
patient. Cessation or a reduction in smoking or chewing of addictive or
psychoactive substances involves the administration of Reboxetine in a
manner and form that provide a reduction in the symptoms of the disease,
or with Tobacco or Nicotine with a reduction in the amount smoked or
chewed. See the general description above for administration of Reboxetine.
II. Attention Deficit Hyperactivity Disorder (ADHD).
ADHD is a condition or disease state that may be treated with Reboxetine.
General descriptions of ADHD, may be found in many standard sources, such
as, The American Psychiatric Press Textbook of Psychiatry, Second Edition,
Edited by Robert E. Hales, Stuart C. Yudofsky, and John A. Talbott,
copyright 1994, incorporated by reference, especially pp. 741 et. al.,
section on "ADHD," incorporated by reference. Another of many
texts is the Manual of Psychiatric Therapeutics, Second Edition, edited by
Richard I. Shader, incorporated by reference, especially Chapter 18,
Attention-Deficit hyperactivity Disorder, and pp. 172 et. seq.,
incorporated by reference.
The treatment of Attention Deficit Hyperactivity Disorder in children and
adults involves the administration of Reboxetine in a manner and form that
provide a reduction in the symptoms of the disease. A child or young adult
may require a smaller dosage depending upon the size, age, condition of
Claim 1 of 7 Claims
What is claimed is:
1. A method of treating or enhancing the treatment of a disorder selected
from Addictive Disorders, Psychoactive Substance Use Disorders,
Intoxication disorders, Inhalation disorders, Alcohol addiction, Tobacco
Addiction and Nicotine Addiction comprising administering a
therapeutically effective, nontoxic dose of reboxetine and derivatives
and/or pharmaceutically acceptable salts thereof to a patient.
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